7CR7

human KCNQ2-CaM in complex with retigabine

7CR7 の概要

• エントリーDOI: 10.2210/pdb7cr7/pdb
• 関連するPDBエントリー: 7CR0 7CR1 7CR2 7CR3 7CR4
• EMDBエントリー: 30448
• 分子名称: Potassium voltage-gated channel subfamily KQT member 2, Calmodulin-3, ethyl N-[2-azanyl-4-[(4-fluorophenyl)methylamino]phenyl]carbamate (3 entities in total)
• 機能のキーワード: ion channel, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 363134.75

構造登録者

Li, X.,Lv, D.,Wang, J.,Ye, S.,Guo, J. (登録日: 2020-08-12, 公開日: 2020-09-16, 最終更新日: 2025-06-25)

主引用文献

Li, X.,Zhang, Q.,Guo, P.,Fu, J.,Mei, L.,Lv, D.,Wang, J.,Lai, D.,Ye, S.,Yang, H.,Guo, J.
Molecular basis for ligand activation of the human KCNQ2 channel.
Cell Res., 31:52-61, 2021

PubMed Abstract: The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper-excitability. A list of synthetic compounds have been developed to directly activate KCNQ2, yet our knowledge of their activation mechanism is limited, due to lack of high-resolution structures. Here, we report cryo-electron microscopy (cryo-EM) structures of the human KCNQ2 determined in apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. The activator-bound structures, along with electrophysiology analysis, reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state, whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation. By accurately defining ligand-binding sites, these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms, but also provide a structural basis for drug optimization and design.

PubMed: 32884139
DOI: 10.1038/s41422-020-00410-8

実験手法

ELECTRON MICROSCOPY (3.7 Å)